Division of Cardiology (P.U., O.O.M., N.A., Q.W., E.D.L., Y.W., J.M.G., O.E.R.G., M.E.A.), The Johns Hopkins University School of Medicine, Baltimore, MD.
Department of Medicine (P.U., O.O.M., N.A., Q.W., E.D.L., Y.W., J.M.G., L.F., M.E.A.), The Johns Hopkins University School of Medicine, Baltimore, MD.
Circulation. 2021 Apr 27;143(17):1687-1703. doi: 10.1161/CIRCULATIONAHA.120.051911. Epub 2021 Feb 17.
Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. -GlcNAcylation (the attachment of -linked β-N-acetylglucosamine [-GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of -GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: -GlcNAc transferase (OGT) and -GlcNAcase (OGA). Failing myocardium is marked by increased -GlcNAcylation, but whether excessive -GlcNAcylation contributes to cardiomyopathy and heart failure is unknown.
We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control -GlcNAcylation independent of pathologic stress.
We found that OGT transgenic hearts showed increased -GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower -GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial -GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in -GlcNAc-mediated cardiac pathology.
Our data provide evidence that excessive -GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of -GlcNAcylation is beneficial against pressure overload-induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive -GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.
心力衰竭是全球范围内主要的死亡原因，与肥胖症、高血压和糖尿病的患病率上升有关。-GlcNAcylation（细胞质、核和线粒体蛋白中β-N-乙酰氨基葡萄糖 [-GlcNAc] 部分的连接）是细胞内蛋白质的一种翻译后修饰，是细胞应激的代谢变阻器。-GlcNAcylation 的总水平取决于营养物质和代谢通量，以及 2 种酶的净活性：-GlcNAc 转移酶（OGT）和 -GlcNAcase（OGA）。衰竭的心肌以增加的 -GlcNAcylation 为特征，但过多的 -GlcNAcylation 是否导致心肌病和心力衰竭尚不清楚。
我们开发了 2 种新的转基因小鼠模型，其心肌过表达 OGT 和 OGA，以独立于病理应激控制 -GlcNAcylation。
我们发现 OGT 转基因心脏显示出增加的 -GlcNAcylation 并发展出严重的扩张型心肌病、室性心律失常和过早死亡。相比之下，OGA 转基因心脏的 -GlcNAcylation 较低，但与野生型同窝对照的心脏功能相同。OGA 转基因心脏对压力超负荷诱导的病理应激具有抗性，应激后心肌 -GlcNAcylation 水平降低，病理肥大程度降低与野生型对照相比。OGT 与 OGA 转基因小鼠的杂交繁殖挽救了心肌病和过早死亡，尽管心肌 OGT 持续升高。转录组学和功能研究显示，OGT 转基因小鼠的心脏存在线粒体能量代谢紊乱，复合体 I 活性受损。复合物 I 活性通过 OGA 转基因杂交繁殖得到挽救，表明线粒体复合物 I 在 -GlcNAc 介导的心脏病理学中具有重要作用。
我们的数据提供了证据表明，过多的 -GlcNAcylation 至少部分导致了心肌病，这归因于能量代谢的缺陷。增强的 OGA 活性具有良好的耐受性，-GlcNAcylation 的衰减对压力超负荷诱导的病理性重塑和心力衰竭有益。这些发现表明，衰减过多的 -GlcNAcylation 可能代表一种治疗心肌病的新方法。
